The homozygous VHL^D126N missense mutation is associated with dramatically elevated erythropoietin levels, consequent polycythemia, and early onset severe pulmonary hypertension

Abstract

von Hippel-Lindau (VHL) protein is the principal negative regulator of hypoxia sensing mediated by transcription factors. Mutations in exon 3 of the VHL gene lead to Chuvash (VHL(R200W)) and Croatian (VHL(H191D)) polycythemias. Here, we describe an infant of Bangladesh ethnicity with a novel homozygous VHL(D126N) mutation with congenital polycythemia and dramatically elevated erythropoietin (EPO) levels, who developed severe fatal pulmonary hypertension. In contrast to Chuvash polycythemia, erythroid progenitors (BFU-Es) did not reveal a marked EPO hypersensitivity. Further, NF-E2 and RUNX1 transcripts that correlate with BFU-Es EPO hypersensitivity in polycythemic mutations were not elevated.

Genetic Evidence of a Precisely Tuned Dysregulation in the Hypoxia Signaling Pathway during Oncogenesis

“…3C), and further studies targeting the genes dysregulated in this context are needed to understand the phenotype observed in homozygotes. In these patients, the exact mechanisms of the occurrence of erythrocytosis (achievement of a threshold that induces HIF and EPO production and/ or direct effect on erythroid progenitors proliferation due to particular properties of the VHL mutations) and occurrence of thrombotic events or PAH still need to be determined (9, 13, 14, 16, 38). Nevertheless, this mutation never induces sufficient selective pressure to allow tumorigenesis and as we evidenced, it may be due to an insufficient dysregulation of the tumorigenic HIF pathway.…”

“…This specific VHL -R200W mutation has also been identified in combination with other VHL mutations (compound heterozygosity) (Supplementary Table S1) and, since then, other missenses VHL mutations have been described (always different from the VHL mutation involved in severe von Hippel-Lindau disease) (Table S2) (12). It is known that the HIF signaling is involved in Chuvash polycythemia (9, 10, 13, 14) but the exact mechanisms that may explain the heterogeneity of the clinical phenotype (differences in serum EPO level and propensity to develop thrombosis and pulmonary arterial hypertension (PAH)) is still unexplained (15, 16). However, a characteristic of these patients is the total absence of tumor development (11, 15, 16).…”

“…It is known that the HIF signaling is involved in Chuvash polycythemia (9, 10, 13, 14) but the exact mechanisms that may explain the heterogeneity of the clinical phenotype (differences in serum EPO level and propensity to develop thrombosis and pulmonary arterial hypertension (PAH)) is still unexplained (15, 16). However, a characteristic of these patients is the total absence of tumor development (11, 15, 16). Noteworthily, the R200W mutation is always transmitted (excepted in one case) (17) within a 340-kilobases haplotype inherited 14,000 to 62,000 years ago from a single founder event (18).…”

Hypoxia and Pulmonary Hypertension

“…VHL mutations are associated with VHL syndrome, which is a hereditary condition, characterised by highly vascularised tumours within speciic tissues, including the renal, retinal and central nervous system [44]. However, a small number of VHL mutations (R200W, D126N, S183L, D126N) are associated with development of Chuvash polycythemia (CP) [45][46][47]. CP is a rare autosomal recessive condition that is endemic to the population in Chuvashia, Russia and in the island of Ischia, Italy [46,48].…”

“…CP is a rare autosomal recessive condition that is endemic to the population in Chuvashia, Russia and in the island of Ischia, Italy [46,48]. Chuvash patients manifest increased haemoglobin and haematocrit with elevated levels of EPO, as well as increased expression of vascular endothelial growth factor (VEGF) and ET-1, which are HIF-α target genes [45][46][47][48][49]. In addition, these patients are highly susceptible to both arterial and venous thrombosis and can develop mild to severe PH [45][46][47][48][49].…”